ABSTRACT The goal of this integrative program project grant, ?Systems Biology of Airway Disease?, is to identify the shared genetic, genomic and epigenetic features between asthma and COPD, two of the most common chronic lung diseases. Aiming to translate human genetics and genomics to biology and eventually benefit disease treatment, this PPG differs from other systems biology proposals because of its comprehensive functional assessment pipelines, which include a series of functional validations on genetic variants, candidate genes and network modules shared between asthma and COPD. Such functional validation will greatly speed up and prioritize candidate disease genes as therapeutic targets. Core C will provide overall functional support to all projects in this PPG. The function of Core C includes: (1) identifying functional GWAS and sequencing variants that are associated with airflow obstruction in both asthma and COPD (Project 1); (2) experimentally validating disease modules built upon genetics, genomics and epigenetics from asthma and COPD subjects (Projects 1,2 and 3); (3) establishing a cellular phenotypic screening model that is relevant to asthma and COPD and applying loss-of-function approach by RNAi in this model to assess novel disease genes (Project 2 and 3); (4) modeling cigarette smoke induced DNA methylome changes in primary human bronchial epithelial cells (Project 3). We will provide needed biological consulting and support to all projects. To fulfill these functions of Core C and, thus, ensure successful completion of this PPG, Core C is assembled with three senior research assistants directed by the experienced cell biologist, Dr. Anny Xiaobo Zhou, the Director of Functional Genomics Laboratory who will be assisted by Dr. Mark Perrella, a senior molecular biologist and pulmonologist in the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, and a longtime collaborator of Dr. Zhou and several other key investigators of the PPG. Core C is based on a well- equipped molecular and cell biology laboratory that has access to all needed resources. In addition, Dr. Zhou has been a longtime collaborator of all Project Principal Investigators, Drs. Scott Weiss, Benjamin Raby and Dawn DeMeo. They have a demonstrated successful track record and productivity that will ensure Core C will meet the overall functional needs of this PPG.